2-bromo-1,1,2,3,3-pentafluoropropane



3,480,683 Z-BROMO-l,1,2,3,3-PENTAFLUOROPROPANE Bernard M. Regan, Chicago, Ill., assignor to Baxter Laboratories, Inc., Morton Grove, 111., a corporation of Delaware No Drawing. Continuation-impart of application Ser. No. 583,523, Feb. 2, 1966. This application Aug. 31, 1967, Ser. No. 664,604

Int. Cl. C07c 17/02, 19/08; A61k 27/00 U.S. Cl. 260-653 Claims ABSTRACT OF THE DISCLOSURE Z-bromo-1,1,2,3,3-pentafluoropropane, useful as a nonflammable inhalation anesthetic which is stable toward soda-lime.

This is a continuation-in-part of co-pending application Ser. No. 538,523, filed Feb. 2, 1966, now U.S. Patent 3,362,874.

This invention relates to a novel bromopentafluoropropane. More particularly, this invention relates to a monobromopentafluoropropane having a bromine atom substituted on the number two carbon atom, namely, 2- bromo-1,1,2,3,3-pentafluoropropane.

It is known that certain halogenated alkanes are useful inhalation anesthetics. Chloroform and halothane are wellknown examples of such compounds which are derivatives of the lower alkanes, methane and ethane, respectively. More recently, it has also been disclosed that certain halogenated fluoropropanes are useful inhalation anesthetics. Thus, Dishart, U.S. Patent 3,034,959, discloses the inhalation anesthetic useof 3-bromo-1,1,2,2-tetrafluoropropane and Belgian Patents 663,478 and 668,605 disclose the inhalation anesthetic use of 3 bromo'3-chloro-1,1,1,2,2- pentafluoropropane.

Position isomers of the monobromopentafluoropropane of the present invention also are known. Thus, 3-bromol,1,1,2,2-pentafluoropropane is disclosed by McBee et al., 77 J. Am. Chem. Socy. 3149 (1955); 3-bromo-1,l,1,3,3- pentafluoropropane is disclosed by Muray, British Patent 908,110; 2-brorno-1,1,l,2,3-pentafluoropropane is disclosed by Rausch et al., 28 J. Org. Chem. 494 (1963); and l-and 3-bromo-l,1,2,2,3-pentafluoropropanes are disclosed in a dissertation by Beck, Reactivities of Aliphatic Fluorides, The Ohio State University (1959).

Two of the above position isomers of the monobromopentafluoropropane of the present invention have been further disclosed as having inhalation anesthetic properties. Thus, Raventos, British Patent 913,143, discloses the inhalation anesthetic properties of 3-bromo-1,1,1,3,3-pentafluoropropane and Burns et al., 17 Anaesthesia 337-343 (1962), disclose the inhalation anesthetic properties of 3- bromo-1,1,1,2,2-pentafluoropropane.

It has now been found that the novel monobro-mopentafluoropropane as defined herein is a useful inhalation anesthetic which has an inhalation margin of safety in mice which is not only substantially higher than the margin of safety of the above-mentioned position isomers disclosed by Raventos and Burns et al., but is also substantially higher than the margin of safety of the inhalation anesthetics in current use, namely, ether, chloroform, and halothane. As such, the novel compound of this invention holds good promise as an effective and useful agent for inducing anesthesia in man.

The novel monobromopentafluoropropane of this invention also is stable to soda lime as distinguished from the position isomer of Raventos, 3 bromo 1,1,l,3,3-penta fluoropropane, which is not stable to soda lime. This property of the novel compound of the present invention makes United States Patent 0 it useful in conventional re-circulation apparatus which employs soda lime for the absorption of carbon dioxide from the patient undergoing anesthesia.

The novel inhalation anesthetic compound of the present invention also has been found to be nonflammable in air and nonexplosive in oxygen at ambient temperatures. Its lower flammability limit in oxygen of about 9% by volume is well above the useful concentrations for inhalation anesthesia in man which is not more than about 5% by volume. Moreover, the flammability margin of safety of the novel compound of this invention is substantially greater than the margin of safety of the position isomer of Burns et al., 3-bromo-1,1,1,2,2-pentafluoropropane.

The novel 2-bromo-1,l,2,3,3-pentafluoropropane of the present invention is a clear liquid at normal room temperature and has a boiling point of 602 C. at 736 mm. Hg. It can be conveniently stored in containers normally used for conventional anesthetics of comparable boiling point, e.g., halothane. It can be administered by apparatus or machines designed for the vaporization of liquid anesthetics and admixtures thereof with oxygen, air or other gaseous mixtures containing oxygen in amounts capable of supporting respiration.

For use in anesthesia, the 2-bromo-1,1,i2,3,3-pentafluoropropane should be free of toxic impurities which may be present according to the particular process used for its manufacture. This compound can, however, be used in admixture with pharmaceutically acceptable diluents and stabilizers, e.g., thymol, or one or more of the known inhalation anesthetics, e.g., nitrous oxide, ether, halothane, chloroform, cyclopropane, methoxyfluorane, and the like.

The novel monobromopentafluoropropane defined herein can be conveniently prepared by elimination of a hydrogen and fluorine from 2 bromo-1,1,3,3-tetrafluoropropane to form the intermediate cisand trans-Z-bromo- 1,3,3-trifluoropropenes, followed by the selective fluorination of the intermediate propene at the double bond.

The starting material, 2 bromo 1,1,3,3-tetrafluoropropane, is a novel compound disclosed and claimed in copending application Serial No. 538,523, filed Feb. 2, 1966. The intermediate propenes also are novel compounds and are disclosed and claimed in co-pending Regan application Ser. No. 664,605, filed concurrently herewith.

A preferred method of preparation of the novel monobromopentafluoropropane of this invention comprises the employment of a mixture of a metal oxide, for example, lead dioxide, and sulfur tetrafluoride for the selective addition of fluorine to the double bond of the 2-brom0-1,3,3- trifluoropropene in an autoclave at a temperature of about C. for about five hours.

Although the above methods of preparation and reaction conditions are specifically described, it will be understood that the novel monobromopentafluoropropane of this invention is not limited to this specific method of preparation. For example, other methods of fluorine addition to the double bond in 2-bromo-1,3,3-trifluoropropene may be employed to prepare the novel anesthetic agent Z-bromo l,1,2,3,3 pentafluoropropane. Thus, elemental fluorine, high valency metallic fluorides (such as, for eX- ample, cobalt trifluoride, silver difluoride, antimony pentafluoride, manganese trifluoride and cerium tetrafluoride), Xenon tetrafluoride or a mixture of lead dioxide and anhydrous hydrogen fluoride and the like can be used to fluorinate the intermediate 2-bromo-1,3,3-trifluoropropenes.

The following examples will further illustrate the present invention, although the invention is not limited to these specific examples. All percentages and parts herein are on a weight basis unless otherwise specified.

3 EXAMPLE 1 Hydrogen at the rate of one-half liter per minute was bubbled through 1,3-dichloro-l,1,3,3-tetrafluoroacetone at 4 C. The mixture of vapors passed through a Pyrex tube (45 cm. x 1.9 cm. I.D.) containing 2% palladium on carbon granules (4-12 mesh) and heated to 200 C. The reaction products were condensed in a trap cooled by Dry Ice. A 750:1 ratio by Weight of dichloro-tetrafluoroacetone to palladium is optimum.

In a typical run 1250 grams (6.28 moles) of dichlorotetrafluoroacetone was vaporized with hydrogen during 22 hours and the mixture passed over 85 grams of palladium-carbon catalyst. Fractional distillation of the reaction products gave 704 grams (5.33 moles, 85% of theory) of crude alcohol (I) B.P. 106109 C., suitable for use in the next step.

Alternatively, the alcohol (I) can be prepared by reduction of 1,l,3,3-tetrafluoroacetone with sodium borohydride. The alcohol (I) obtained in this manner had B.P. 107-09 C., 11 1.333. The identity of the alcohols prepared in these two ways was confirmed by infrared spectra.

EXAMPLE 2 1, 1 ,3,3,-tetrafiuoro-2-propyl p-toluenesulfonate (II) A mixture of crude l,1,3,3-tetrafluoropropan-2-ol (I) (315 g., 2.4 moles), p-toluenesulfonyl chloride (460 g., 2.4 moles) and 600 ml. of water was stirred as N sodium hydroxide (514 ml., 2.57 moles) was added during 1.5 hours, and the temperature was maintained between 25 C.-40 C. Stirring was continued for 16 hours. The lower layer of crude ester (II) was separated, stirred, evacuated to between 25-40 mm. Hg and heated to 125 C. until volatile impurities ceased to be removed. Five hundred eighty-three grams (2.04 moles, 85% of theory) of crude ester (II) suitable for use in subsequent steps was obtained. Crystallization from ligroin gave ester (11), M.P. 31 C., H 1.466.

Analysis.--Calcd. for C H F O S: C, 41.91%; H,

3.52%; S, 11.20%. Found: C, 42.13%; H, 3.63%; 5, 10.95%.

EXAMPLE 3 Z-bromo-1,1,3,3-tetrafluoropropane (III) To a stirred mixture of potassium bromide (357 g., 3.0 moles) in 700 ml. of diethylene glycol heated to between 200-210 C., crude 1,1,3,3-tetrafluoro-2-propy1 p-toluenesulfonate (II) (572 g., 2.0 moles) was added during 1.5 hours. The vapors of III rose through a Vigreaux distilling column and descended through a cold-water spiral condensor. The liquid product was collected in an icecooled receiver for 1.5 hours after the addition of ester (II) was completed. The liquid product was chiefly a mixture of III, 1,4-dioxane and water, from which the III was purified by successive washings with water and aqueous 60% sulfuric acid. It was neutralized by a wash with cold dilute aqueous sodium hydroxide. The crude bromide (III) amounted to 314 grams (81.5% of theory). Fractional distillation gave 256 grams of bromide (III), R 82.6-82.8 C. Pure (99.9% by G.L.C.) bromide (III) has H. 83 C., d3 1.8743, n 1.3691 and a vapor pressure of 57 mm. Hg at C. Its vapor pressuretemperature equation is Its 60 me. nuclear magnetic resonance (NMR) and infrared spectra confirmed the CHF CHBr--CHF structure.

log P 8.1590

EXAMPLE 4 Cisand trans-2-bromo-1,3,3-trifiuoropropenes (IV) A mixture of 2-bromo-1,1,3,3-tetrafluoropropane (III) (368 g., 1.88 moles) and low-moisture (about 2% water) soda lime (180 g.) was heated to boiling under total reflux for about sixteen hours. Gas-liquid chromatographic, infrared, and proton nuclear magnetic resonance analyses of the liquid reaction product showed essentially complete conversion to a mixture of cisand trans-2-bromo- 1,3,3-trifluoropropenes (IV). The ratio of the cis and trans-propene isomers produced was about 13: 1. The predominant propene has a longer retention time than either the other propene or the starting propane on a column packed with 20% diisodecylphthalate on Chromasorb P at C. to C. Fractional distillation of the propene mixture did not afford an efficient separation, and the cis and trans-propene isomers distilled concurrently, B. 77.5-78.0 C. (290 g., 1.66 moles, 88% yield). The last fraction collected afforded the purest product, B 78.0 C., d 1.8429, 21 1.3961, and is 99.4% the predominant propene and 0.54% the other propene.

EXAMPLE 5 2-bromo-1,1,2,3,3-pentafiuoropropane (V) A 300 ml. Hoke high pressure (5,000 p.s.i.) cylinder equipped with a 2,600 to 3,000 p.s.i. rupture disc assembly and a Hoke M327A needle valve was charged with 48.6 grams of PbO After pressure checking the system at p.s.i., the contents were thoroughly vacuum degassed while the cylinder was heated externally. Next, 23.6 grams of 2-bromo-1,3,3-trifluoropropene (IV) were distilled in on a high vacuum system after which the vessel was allowed to warm to ambient temperature. This warming procedure is believed to be desirable since the olefin can then act as a reaction medium and heat sink for the exothermic reaction of Pb0 and SP carried out in the next step. The vessel was then precoo'led to 196 C. and 38 ml. SR; (73 g., at 78 C.) were distilled in, after which the vessel was allowed to warm very slowly to ambient temperature by placing it in a cold Dewar flask. The next morning the cylinder was placed in a rocking furnace, warmed to 100 C., and rocked for five hours. After cooling, the volatile contents were removed under vacuum through traps at 78 C. and 196 C. placed in series. The 78 C. trap usually contained 24 to 26 grams of product which analyzed from 75 to 95% 2- bromo-l,l,2,3,3-pentafluoropropane by gas chromatography. Extraction of this product with dilute aqueous alkaline sodium sulfite drying of the washed product, and fractional distillation gave 2-bromo-1,1,2,3,3-pentafluoropropane; B 60.2 C., r1 1.86, having a purity of 99.9% as determined by gas-liquid chromatography. The molecular structure CHF -CFBr-CHF was confirmed by proton nuclear magnetic resonance and infrared spectra.

EXAMPLE 6 Inhalation of the vapor of 2-bromo-1,1,2,3,3-pentafluoropropane admixed with air in the manner described by Robbins, 86 J. Pharmacol. Exper. Therap. 197-204 (1946), produced anesthesia in white mice. The minimum concentration by volume percent required to produce full anesthesia (loss of negative righting reflex) in 50% of the test animals in five minutes, AC and the minimum concentration by volume percent required to kill 50% of the test mice in five minutes, LC are given in Table I, below. The inhalation margin of safety as measured in mice by the ratio LC /AC is also given in Table I. For purposes of comparison, similar data which were obtained under the same conditions as for the above compound are given for three inhalation anesthetics in current use, namely, ether, chloroform and halothane, and for the position isomers 3-bromo-1,1,1,2,2-pentafluoropropane and 3-bromo-1,1,1,3,3-pentafluoroproprane disclosed by Burns et al., and Raventos, respectively, as having inhalation anesthetic properties. The number of mice used with the different anesthetic agents varied from 25 to 92 for determining each of the AC and L0 doses.

TABLE I.INI-IALATION ANESTHESIA IN MICE The results set forth inthe above table show that the novel bromopentafluoropropane of this invention is both more potent and has a substantially greater inhalation sence of soda lime. The chromatographic results are given in Table II, below, in which RT. is retention time in minutes from air and Area percent is 100 times the ratio of the area under a peak to the total area under all peaks in the recorded chromatogram. A column ten feet long and A inch in diameter packed with diisodecylphthalate on 80-100 mesh firebrick and a thermoconductivity detector were employed in this study. For purposes of comparison, similar data which were obtained under the same conditions as for the above compound are given for halothane.

TABLE II.-SODA LIME STABILITY OF ANES'IHETICS margin of safety than any of the three inhalation anesthetics in current use or either of the two position isomers heretofore disclosed as having inhalation anesthetic properties.

EXAMPLE 7 Surgical anesthesia (stage III, plane 2) was induced in two dogs with about 3% by volume of 2-bromo-l,l,2,3,3- pentafluoropropane in oxygen and maintained for 30 to 60 minutes with about 1.5% to 2.5% by volume of this anesthetic agent in oxygen. For purposes of comparison, surgical anesthesia was induced in four dogs with 2% to 4% by volume halothane in oxygen and maintained for 60 minutes with 1% to 2% by volume of halothane in oxygen.

\ The anesthetic agent was administered via an endotracheal catheter with inflation cuffs in a non-rebreathing system subsequent to initial anesthesia with sodium methohexital and pretreatment with atropine sulfate and heparin.

Heart rate and myocardial responses were determined from EKG records. Spontaneous respiratory rate and respiratory minute volume were maintained by means of a pressure change transducer and a wet-test meter, respectively. The arterial blood pressure was monitored, and blood samples were withdrawn for determinations of blood gases and pH.

, Anesthesia with 2-bromo-l,1,2,3,3pentafluoropropane in two dogs was equivalent to halothane anesthesia. Both compounds produced a fall in diastolic blood pressure below 70 mm. Hg, and a decrease in heart rate. However, normal spontaneous respiratory rate and minute volume and normal pCO values were observed in anesthesias with both compounds. The EKG records were also normal with the exception of T-wave inversion during anesthesia with both compounds.

EXAMPLE 8 The soda lime stability of the novel inhalation anesthetic of the present invention was determined essentially according to the procedure of Glover and Hodgson, l6 Anesthesia 19-23 (1961). The liquid anesthetic (0.65 ml.) and soda lime (0.50 g'., 8-12 mesh, l5%20% by weight of water) were sealed in a glass ampule and heated at 70 C. for three hours and then analyzed by gas-liquid partition chromatography. For purposes of comparison, a liquid anesthetic blank was treated in the same way in the ab- The remarkable soda lime stability of the novel monobromopentafluoropropane of this invention is shown by the high correspondence between the 999+ and 99.5 Area percents after 7.5 minutes of retention time in the blank sample and the soda lime treated sample, respectively.

EXAMPLE 9 The flammability of gaseous mixtures of the novel inhalation anesthetic of the present invention and air or oxygen was determined at room temperature and atmospheric pressure by visualization of the downward propagation of a flame in a glass bottle having a cylindrical portion 2.3 inches ID. x 3.5 inches in height. The bottle was flushed with pure oxygen or air, a known quantity of liquid anesthetic was added rapidly, and the bottle was closed with a ground glass stopper. The bottle was then rotated and shaken until the liquid anesthetic was completely vaporized and uniformly mixed with oxygen or air. The stopper was then removed and immediately a burning stick inserted in the bottle 1.5 to 2.0 inches below the bottle mouth.

The concentration by volume percent of the gaseous anesthetic in oxygen or air was calculated by well-known computation means employing the known volume of the stoppered bottle (i.e., the volume of the contained oxygen or air), the known volume of the added liquid anesthetic, the known densities and molecular weights and application of the ideal gas law to compute the gaseous volume of the anesthetic sample.

The lower flammability limits in oxygen, LFlO and in air, LFl Air, as determined by the above procedure are given in Table III, below. These flammability limits are stated as a range of two concentrations by volume percent; downward flame propagation was observed at the higher concentration but not at the lower concentration of the anesthetic in the gaseous mixture. The median anesthetic concentration for mice, AC as determined in Example 6, above, is also given in Table III. The ratio, LFlO /AC herein referred to as the flammability margin of safety, is also given in Table III. For purposes of comparison, similar data which were obtained under the same conditions as for the above compound are given for the position isomer 3-bromo 1,l,l,2,2 pentafiuoropropane, which has been previously disclosed as having inhalation anesthetic properties.

TABLE III.FLAMMABILITY OF ANES'IHETICS CFz-CFzCH2Br 11.0-11.6 Nonflamm The results set forth in the above table show that the novel bromopentafluoropropane of this invention has a substantially greater flammability margin of safety than shown by the position isomer 3 bromo 1,1,1,2,2 pentafluoropropane.

As will be readily apparent to those skilled in the art, other examples of the herein-defined invention can be devised after reading the foregoing specification and claims appended hereto by various modifications and adaptations without departing from the spirit and scope of the invention. All such modifications and adaptations are included Within the scope of the invention as defined in the appended claims.

What is claimed is:

1. A method of inducing anesthesia in animals which comprises administering to said animals an efiective amount of 2-bromo-1,1,2,3,3-pentafluoropropane.

2. The method of preparing 2-bromo-l,l,2,3,3pentafluoropropane which comprises the addition of fluorine to the double bond of 2-bromo-1,3,3-trifluoropropene.

3. The method of preparing 2-bromo-1,1,2,3,3-pentafluoropropane which comprises the addition of fluorine to the double bond of 2-bromo-1,3,3 trifluoropropene by employing a mixture of lead dioxide and sulfur tetrafluoride.

4. The method of preparing 2-bromo-1,1,2,3,3-pentafluoropropane which comprises the addition of fluorine to the double bond of 2-br0mo-1,3,3-trifluoropropene With material selected from the group consisting of (A) a mixture of lead dioxide and sulfur tetrafluoride,

(B) elemental fluorine,

(C) high valency metallic fluorides selected from the group consisting of cobalt trifluoride, silver difluoride, antimony pentafluoride, manganese trifluoride and cerium tetrafluoride,

(D) xenon tetrafluoride and (E) a mixture of lead dioxide and anhydrous hydrogen fluoride.

5. The method of preparing 2-bromo-1,l,2,3,3-pentafluoropropane which comprises the selective fluorination at the double bond of 2-bromo-1,3,3-trifluoropropene by employing a mixture of lead dioxide and sulfur tetrafluoride at a temperature of about 100 C. for about five hours.

References Cited UNITED STATES PATENTS 2,545,430 3/1951 McBee et al. 260653 3,097,133 7/1963 Suckling et al. 260653 3,177,260 4/1965 Muray et al. 260653 3,332,840 7/1967 Regan 260653 3,362,874 1/1968 Regan 16752.6 2,413,696 1/1947 Downing et al. 260653 DANIEL D. HORWITZ, Primary Examiner US. Cl. X.R. 424-350 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 37 480 533 Dated November 25. 1970 Invent0r(S) Bernard M, Regan It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the claims, cancel claim 1, at col. 7, line 15,

which reads as follows:

"1. A method of inducing anesthesia in animals which comprises administering to said animals an effective amount of Z-bromo-l, 1, 2, 3, 3-pentaf1uoropr0pane. and insert the following claim:

--1. Z-bromo-l, 1, 2, 3, 3-pentaf1uoropropane.

SIGNED AND SEALED Eavmdunuhqkmm 3. 8- Gomissiom 01 ml ORM PO-IOSO (IO-69) 

